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Aisalingb O’Dwyer, an associate in the IP team and Frances Denney, a trainee patent attorney, comment on the decision of the UK Supreme Court in the matter of Actavis Group PTC EHF & Ors v ICOS Corp & Anor [2019] UKSC 15.

When is clinical research obvious?  The Supreme Court was asked to decide in November 2018, when it heard the appeal by Actavis Group PTC EHF & Ors (the respondents) v ICOS Corp & Anor (the appellants).

Background

ICOS is the owner of the European patent at issue (EP1173181 – the “181 Patent”). Eli Lilly (the second appellant) is the exclusive licensee.

The 181 Patent is directed to the use of tadalafil in a 1 to 5mg dosage form for the treatment of erectile dysfunction (ED). Tadalafil is the generic name for the drug Cialis, which is used to treat ED as an alternative to sildenafil (more commonly known by its brand name, Viagra). The alleged essence of the 181 Patent invention is the discovery that tadalafil is effective in treating ED at such a low dose and with minimal side effects. This discovery has allowed the drug to be taken daily rather than on demand. However, tadalafil had already been the subject of an earlier patent (the “Daugan” patent, transferred to ICOS from GlaxoSmithKline) which disclosed the use of tadalafil in the treatment of ED, albeit at higher dosages than envisaged by the 181 Patent.

In 2016, the Respondents (Actavis, Teva and Generics UK t/a Mylan) started proceedings to “clear the way” and revoke the 181 Patent, with the intention of launching their own generic products.

The central question of the proceedings was whether, in light of the common general knowledge and Daugan as the closest prior art, the claims of the 181 Patent were obvious.

Earlier decisions

  • High Court

At first instance, Birss J found the 181 Patent to be valid and infringed [2016] EWHC 1955 (Pat).

Birss J considered that, based on Daugan, it would have been entirely obvious for a skilled team to set out to take tadalafil forward into a routine pre-clinical and clinical trial programme (Phases I-IV) as an oral treatment for ED at the priority date.

Looking to carry out Phase IIb (and specifically determine the dose-response relationship), Birss J considered that, again based on Daugan, the skilled team would likely carry out a first dose ranging study of “on demand” and “daily” dosing using 25, 50 and 100mg of tadalafil. At these doses, the skilled team would have found an apparent therapeutic plateau, i.e. no difference in efficacy between the three doses. It was accepted this result would be unexpected.

The critical point was whether, in light of this finding, it would be obvious for the skilled person to conduct further dose ranging studies at lower doses to determine the minimum effective dose, which would lead to the dosage regimen of the 181 Patent – 1 to 5mg of tadalafil. This process would require the skilled person to make “value judgements”.

Birss J concluded that it was “very likely” that the skilled team would conduct such further lower dose studies.

However, Birss J further considered that, a 5mg/day dose would not have been tested with a reasonable expectation of success given the teachings in Daugan, which only exemplified 50mg doses. A 5mg/day dose is significantly lower than the 50mg starting point and also provided a surprising result – efficacy with reduced side effects. In addition, the skilled team needed to make many “value judgements” to arrive at the invention.

Thus, Birss J concluded that the claims of the 181 patent involved an inventive step.

  • Court of Appeal

The Respondents appealed the decision on five grounds, including obviousness in view of Daugan.

The Court of Appeal, composed of Kitchin LJ, Floyd LJ and Lewison LJ allowed the appeal on the ground of obviousness, and declared the 181 Patent invalid [2017] EWCA Civ 1671.

Kitchin LJ generally agreed with the reasoning of Birss J, until it came to considering the actions of the skilled team once the therapeutic plateau had been identified.

Kitchin LJ referred to Birss J’s findings that it would have been “very likely” lower doses would have been investigated once the therapeutic plateau was discovered as the purpose of the Phase IIb study would not have been fulfilled otherwise.  This was supported by expert evidence that it would have been a “no brainer” for the skilled team to conduct further lower dose studies. Kitchin LJ therefore rejected Birss J’s conclusion that the skilled person would be faced with multiple parallel avenues of possible studies and would have to make multiple value judgements to arrive at the invention.

Kitchin LJ also considered Birss J should not have attached any weight to the 5mg dose being considerably less than 50mg, or that the 5mg dose had an unexpected effect of reduced side effects, this was a bonus effect, which did not cause the 5mg dose to cease to be obvious.

Kitchin LJ thus concluded that the skilled but unimaginative team would embark on a clinical trial process with a reasonable expectation of success, and in the course of doing so would have arrived at the claimed invention.

Decision of the Supreme Court

The Supreme Court composed of Lady Hale (President), Lord Kerr, Lord Sumption, Lord Hodge and Lord Briggs unanimously dismissed the appeal.

The Court was satisfied that the Court of Appeal was entitled to interfere with the trial judge’s assessment of obviousness and to hold that the 181 patent was invalid for lacking an inventive step.

  • Reversal of trial judge’s evaluation

The Court determined that the Court of Appeal was entitled to reject Birss J’s evaluation of the181 Patent. The Court held that the Court of Appeal did not reverse any of Birss J’s findings primary of fact, but correctly highlighted the failure of Birss J to appreciate the logical consequences of said findings – that is it was “very likely” that the skilled team would continue low dose testing. This is an error of principle, which thus allows an appellate court to carry out its own evaluation.

  • Obviousness

The Court generally agreed with the Court of Appeal, although the Court developed its own reasoning as to why the claims lacked an inventive step in view of Daugan.

Lord Hodge, with whom the other Lords concurred, considered ten factors relevant to the case, although this was non-exhaustive:

  1. whether something was “obvious to try” at the priority date;
  2. the routine nature of the research and established practice of following such research;
  3. the burden and cost of the research programme;
  4. the necessity for and the nature of value judgements;
  5. alternative or multiple paths of research;
  6. the motive of the skilled person;
  7. whether the results of research are unexpected;
  8. hindsight;
  9. whether a feature of a claimed invention is an added benefit in a context in which the claimed invention is obvious for another purpose; and
  10. dosage patents with EPC 2000/Swiss-style claims may be valid.

In view of these factors, the Court held the skilled team was engaged in the familiar and routine testing required to establish the appropriate dosage regime for tadalafil, in order to implement Daugan. It was obvious to embark on that exercise and carry out tests in a routine way until an appropriate dose was ascertained. Those tests included the completion of the dose-ranging studies, which was the purpose of Phase IIb. The fact a 5mg dose of tadalafil remained effective as a treatment of ED but also had the additional and unexpected result of reduced side effects was an added benefit. This did not prevent the identification of 5mg as the appropriate dose from being obvious. The invention was arrived at due to completion of the required Phase IIb dose ranging studies.

Comment

This case provides an important update on how the UK Courts view the patentability of necessary or routine investigations.  Significantly, the Court did not find that the product of such enquiries can never be inventive. Lord Hodge recognised that “efficacious drugs discovered by research involving standard pre-clinical and clinical trials should be rewarded with a patent if they meet the statutory tests”. The relevant statutory requirement is that an invention involves an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art.

Significantly, a large number of dosage regimen patents may now be vulnerable in the UK.  Whereas previously a selection or undertaking of multiple non-inventive steps might, in combination, be deemed inventive because the invention was not directly obtainable from the closest prior art, Lord Hodge’s approach makes it clear that this is no longer the case.  Applicants will need to consider if their invention is obvious on a case by case basis, a position advocated by The IP Federation, the British Generic Manufacturers Association and the UK BioIndustry Association, who intervened in the case.

The ten factors set out in Lord Hodge’s judgment are likely to assist parties in assessing their invention, though no one factor is of overriding importance.  Rather, the inventive step will be assessed in light of all the circumstances. However, the extent to which this this approach will be extended to patents beyond those for dosage regimes remains to be seen.